Studies of the escape of solutes from plasma usually consider the capillary wall to be the primary barrier to movement. However, recent physiological and physicochemical studies on the interstitial macromolecules have strongly suggested that the tissue matrix might contribute significantly to the transport resistance. There are data which cannot be explained by the conventional view, but which are easily understood if the tissue matrix were an important barrier to solute movement. The delay observed in the development of osmotic pressure by large proteins in the isogravimetric hind-limb preparation is such a phenomenon. The research will test the hypothesis that the interstitial matrix provides a graded restriction to diffusion and is the principal osmotic barrier by investigating: 1) the variation in the development time of osmotic pressure with solute size, 2) the diffusional loss rates of extracellular solutes from the perfusate, and 3) the variation of the capillary filtration coefficient with the protein content of the perfusate. If the hypothesis proves to be correct, this will necessitate a major change in our view of the capillary wall and the control of permeability.